Project Summary A timely antibody response is critical to host defense against viral infections. Antibodies that directly neutralize viruses or function through Fc-dependent mechanisms are produced in response to viral infections by subsets of B cells located in specific tissue compartments. The genesis of a protective humoral response to viral infection is incompletely understood. Mice deficient in Mmp7, which encodes matrix metalloproteinase 7 (MMP7), fail to mount a timely, protective humoral response and succumb to enteric viral infection. We hypothesize that a critical function of MMP7 is to process the precursor forms of enteric alpha-defensin antimicrobial peptides into mature, functional peptides, which then function as adjuvants. However, the available data does not exclude additional roles for MMP7 in B cell function. To identify the mechanism whereby MMP7 deficiency alters the humoral response to enteric viral infection, we will create tissue-specific Mmp7 knockout (on a wild type background) and expression (on a knockout background) mouse models to identify tissues in which MMP7 is both necessary and sufficient for a wild type, protective antiviral immune response to enteric viral infection. The conditional knockout model will also function as an Mmp7 reporter, which will allow for the identification of Mmp7-expressing cells within these tissues. Creation of these mouse models will be valuable to the broader scientific community, since MMP7-dependent functions are important in multiple aspects of epithelial biology including immunity, damage repair, and tumor biology. The results of these studies will enable future efforts to identify the molecular mechanisms for MMP7-dependent functions in humoral immunity, which will have broad impact on our understanding of viral diseases and the design of vaccines to elicit humoral immunity.